In animals, the hormone, melatonin, plays an important role as a chemical mediator of the effects of season on behavior. In many instances, changes in the length of the night serve as the environmental signal that triggers seasonal changes in behavior. Melatonin is secreted exclusively at night, and the duration of its secretion varies with seasonal variations in the length of the night. Because of these properties, many organisms use changes in the duration of nocturnal melatonin secretion as a chemical cue to trigger changes in functions, such as breeding, that vary on a seasonal basis. Our recent research (Z01 MH 02424-01 CP) showed that humans, in the course of their evolution, have conserved brain mechanisms similar to those that exist in animals that enable them to detect seasonal changes in night-length and modify the duration of nocturnal melatonin secretion. Human responses to change in photoperiod were detected in experimental conditions in which individuals were exposed to long and short artificial "days". In a subsequent experiment (Z01 MH 02424-01 CP) we investigated whether healthy individuals living in a modern, urban environment (metro Washington, DC area), in which they are routinely exposed to artificial light, are still able to detect seasonal changes in the duration of the night and to respond to these changes by modifying the duration of the nocturnal period of melatonin secretion. We found that patterns of nocturnal melatonin secretion in women responded to seasonal changes in the duration of the night, while those in men did not. This finding suggests that there may be gender differences in responsiveness to artificial light of mechanisms that track seasonal changes in the length of the night. Because of the importance of the duration of nocturnal melatonin secretion as a transducer of the effects of seasonal changes in the length of the night on animal behavior, it would be important to investigate whether melatonin plays a role in the pathogenesis of seasonal affective disorder (SAD) with recurrent winter depression. Accordingly, in this project, we are assessing whether or not the duration of nocturnal melatonin secretion varies on a seasonal basis in women with SAD, as it does in healthy women. In 28 patients and 30 matched controls, melatonin was abnormally unresponsive to change of season in women with SAD, raising the possibility that SAD results when the pineal gland fails to exhibit a seasonal response that normally occurs in healthy women. In contrast, 9 patients and 15 matched controls, we found that melatonin is responsive to change of season in men with SAD but not in healthy men, a result that is consistent with the classic hypothesis that changes in duration of melatonin secretion trigger winter depression in SAD. The number of male subjects will be increased during the next two years to rule out Type II error. An important post hoc finding in these studies was that seasonal changes in the intrinsic duration of nocturnal melatonin secretion are almost entirely a function of seasonal changes in the timing of morning offset of secretion. This finding indicates that the degree to which individuals' melatonin secretion responds to seasonal changes in night length as a function of their exposure to, or processing of, morning light. This finding provides an important clue in our quest to understand why some individuals respond to change of season while others do not.